The Pathway Less Traveled

August 27, 2004: Astronauts have long known that
space travel is a good way to diet. The excitement of launch. Thrilling
vistas seen from Earth orbit. Floating weightless. Maybe a touch of
motion sickness. Who can eat at a time like that?

Rats, apparently, feel the same way. Rats in space (they've been
there onboard the space shuttle) also under-eat. They grow lean compared
to rats on Earth. Curiously, rats experiencing high gravity (inside
gently-spinning centrifuges) under-eat, too. And this suggests there's
more to the story than thrilling vistas:

"Altered
gravity somehow disrupts the natural ability of animals to maintain
their own weight," says Barbara Horwitz, a professor of physiology
at the University of California. No one understands exactly why that
should be, but it's probably an important clue to the inner workings
of weight control--something that interests people on Earth just as
much as astronauts in space. Horwitz is studying the phenomenon in
rats at her laboratory in Davis, California.

Although some of us who struggle with weight issues may find it hard
to believe, animals, including humans, have evolved a complicated system
for maintaining appropriate weight. You'd expect that: the bodies of
animals that are too heavy, or not heavy enough, don't function properly.

Feeding behavior is essential, not only to the health of individuals,
but also to the survival of whole species. The body stores energy
in fat, and there's a minimum amount an organism must have before
it can get pregnant. "Animals that lose a lot of fat don't reproduce,"
says Horwitz.

But the complex network that signals when to eat and when to stop
eating can go awry. This could be a contributing cause of, e.g.,
the "obesity epidemic" in the United States, under-eating
among astronauts, and maladies such as the "wasting syndrome"
linked to AIDS.

Horwitz is particularly interested in leptin regulatory pathways.
Leptin is a hormone that's key to regulating appetite: when it was
first discovered in the mid-1990's it was regarded as a possible way
to treat obesity in humans. Leptin is produced by fat cells. The more
fat cells an organism has, the more leptin circulates through its
body.

Leptin manages appetite by activating receptors in the hypothalamus,
a part of the brain. These receptors control the production of small
signaling proteins called neuropeptides. Leptin increases the amount
of neuropeptides that make you feel full, and decreases the amount
of neuropeptides that make you feel hungry.

Left:
An artist's concept of the brain-body appetite control system. Copyright:
Mediagnost. All rights reserved.

Horwitz is studying leptin regulatory pathways in rats: The animals
live in a 2-g (twice normal gravity) centrifuge in individual,
free-swinging cages, for as long as eight weeks. Even though they're
working against twice the gravity they're used to, the rats don't
seem to mind. They move around, they groom themselves. If they're
allowed, they'll even breed on the centrifuge, says Horwitz.

Living in double gravity naturally requires more energy. The rats
were offered all the food they wanted, yet, at first, they ate less
than they needed to maintain their body mass--much like astronauts
in low gravity.

Horwitz and colleagues tested the rats (along with 1-g control
groups) at 1, 2 and 8 weeks. During the first week, some of the rats'
neuropeptides were mixed up. One, in particular, which stimulates
feeding and therefore should have increased, actually went down.

By the eighth week, things were back to normal--almost. The animals
produced the same amount of neuropeptides in both 1-g and
2-g habitats. Double-gravity rats were finally eating as
much as they needed. But they remained lean: they never regained the
fat they lost at the beginning of the study.

"That means that the pathway somehow was changed," says
Horwitz. "The relationship between the amount of fat, and how
much leptin was secreted, and the functioning of the feedback system
is altered in high gravity."

Horwitz hopes to pinpoint the exact mechanisms by further testing
the rats' genes: Each neuropeptide in the appetite feedback loop is
produced or "expressed" by a gene that has been activated.
Using a technology called DNA microarrays, Horwitz and colleagues
examine thousands of rat genes at a time. They can see which genes
have been activated, and how active they are.

Understanding
the chemical pathways at this basic level could lead to "countermeasures,"
i.e., treatments to restore broken leptin regulatory systems.

Right:
Prof. Barbara Horwitz of the University of California, Davis. [More]

Many researchers now believe that leptin's main role in humans is
protecting against weight loss more so than weight gain. It makes
sense: food surpluses are a relatively new phenomenon. Humans have
evolved to withstand deprivation, not excess.

This makes leptin, potentially, even more important to astronauts:
It's part of a regulatory pathway that keeps them from becoming too
lean when stress, motion sickness and bland food take away their appetites.

Horwitz's research is important here on Earth, too. People with weight
control problems like obesity may have defective leptin regulatory
pathways: they tend to have plenty of leptin coursing through their
bodies, but it does not cause them to eat less. The big question is
why. Maybe their leptin receptors don't work well, or their neuropeptides
aren't produced properly. Or it could be something else entirely.